Retinoids, natural and synthetic analogues of vitamin A, play a major role in controlling cell proliferation, differentiation, embryonic development and apoptosis. All-trans-Retinoic acid (ATRA), 13-cis-retinoic acid, and synthetic analogues are widely used for topical and oral administration in the management of dermatological diseases such as acne, psoriasis, and other disorders in which abnormal patterns of keratinization are found. Many biological effects of retinoids are mediated by the activation of a family of gene transcription factors known as Retinoic Acid Receptors (RARs) and Retinoid X Receptors (RXRs). Each class is composed of three distinct receptor subtypes (α, β and γ). After complexation with a ligand, RARs exert their gene transcriptional activity by forming a heterodimer with Retinoid X Receptors (RXRs). Side effects such as mucocutaneous irritation, hypervitaminosis A, and teratogenicity are drawbacks in the therapeutic use of retinoids.
The discovery of RAR and RXR subtypes has stimulated medicinal chemists to seek novel subtype-selective drugs with improved therapeutic indices. In normal skin, RAR-α□ and predominantly RAR-γ are present in the keratinocytes of the epidermis. RAR-β is neither expressed nor induced in this skin layer. In contrast, in the dermis, the fibroblast does express RAR-β and in addition the gene encoding RAR-β is also inducible by retinoic acid in this cell type. Consequently, in the field of dermatology, selective compounds for the RAR-γ subtype act preferentially in the epidermis, while RAR-β mediated action leads to response in fibroblasts; therefore, for skin disorders that involve the RAR signaling pathway, molecules with mixed RAR-β/γ profiles are preferred.
Cancer is a complex disease characterized by genetic mutations that lead to uncontrolled cell growth. Cancerous cells are present in all organisms and under normal circumstances their excessive growth is tightly regulated by various physiological factors. One such regulatory process is apoptosis or programmed cell death. When the internal machinery of a cell detects abnormalities in cell division and growth, a signal is propagated within the cell, activating suicide proteins that kill the afflicted cell and prevent its proliferation. Such an apoptotic signal can be triggered, for example, when a ligand or drug interacts with a receptor or protein in the cell.
Most agents that induce apoptosis in cancer cells (e.g. Doxorubicin and Vincristine) are extremely toxic and cause a number of undesirable side effects. The toxicity associated with these therapies is a result of the non-specific interaction of the drug with the DNA of non-cancerous cells (e.g. intestinal and red blood cells). In order to circumvent such undesirable side effects, more selective compounds have been designed that inhibit one or more signaling proteins, growth factors and/or receptors involved in cancer cell proliferation. Examples include monoclonal antibodies for breast cancer (e.g. Herceptin) and Non-Hodgkin's Lymphoma (e.g. Rituxan), as well anti-angiogenic drugs for chronic myeloid leukemia (e.g. Gleevec). Since patient populations are genetically heterogeneous, it follows that a single selective therapy will not work in all cases, and as a result, cancer drugs are often used in combination. As such, there is a continual need for improved treatments.
Clinical studies have shown that retinoic acid and its synthetic analogs can inhibit the growth and invasion of cancer cells, and induce them to undergo apoptosis, thereby eradicating various types of cancers.
The novel compounds of this invention modulate the activity of Nuclear Retinoid receptors. These novel compounds are thus useful for regulating cell differentiation and cell cycle processes as well as other cellular signaling processes controlled or regulated by hormones and vitamins such as the thyroid hormone, vitamin D, all-trans retinoic acid and 9-cis-retinoic acid. Hence, conditions and/or diseases that are regulated by the aforementioned entities may be treated using the compounds of this invention. Examples of such conditions include for example cancer, mammary cancer, prostate cancer, kidney cancer, Karposi's sarcoma, colon cancer, cervical cancer, lung cancer, cutaneous T-cell lymphoma, cancer of the head and neck, cancers of the aerodigestive pathway, skin cancer, bladder cancer, sarcomas, leukoplakias, acute promyelocytic leukemia, acne, psoriasis, aging, wrinkling, diabetes, hyperglycemia, bone calcification, thyroid conditions, and the like.
Compounds that modulate the activity of RAR receptors are structural analogs of all-trans-retinoic acid. On the other hand compounds that modulate the activity of RXR receptors are structural analogs of 9-cis-retinoic acid (e.g. Bexarotene). The aforementioned modulators of Nuclear Retinoid receptors bear a carboxylic acid group in a specific position of the molecule. This acidic group forms a salt bridge to a basic residue in the binding pocket of the Nuclear Retinoid receptors. Research in this field indicates that removal of this acidic group drastically reduces the potency or the modulator. There are however, other amino acid residues in the binding pocket that can interact with the modulator. None of the modulators of Nuclear Retinoid receptors described to date take advantage of these critical interactions.
Another drawback of the current state of the art is the limited aqueous solubility of the selective Nuclear Retinoid receptor modulators. Said modulators mimic the structures of retinoic acids in order to conform to the three-dimensional structure and the hydrophobic nature of the respective binding pockets. In general, introduction of solubilizing substituents has resulted in lower in vitro binding affinity or increased in vivo metabolism and toxicity.
For treatment of skin disorders such as acne and psoriasis, agents are needed that can help alleviate the symptoms of the disorders without irritating the skin. Another drawback of the current state of the art is the low pKa of the carboxylic acid residue present in the selective Nuclear Retinoid receptor modulators. When applied topically, this acidic residue can lower the pH of the skin and in turn cause redness and irritation of the dermis.
Another major drawback of the current state of the art is the teratogenicity of currently prescribed retinoid acne medicines such as Differin® and Accutane®. In addition, Accutane® has also been associated with an increased risk of suicidal thoughts or actions (FDA Isotretinoin patient information sheet, August 2005). Studies have shown that certain modifications of the all-trans-retinoic acid backbone, specifically the carboxylic acid functional group, can produce non-teratogenic retinoid analogs that retain their pharmacological activity (Willhite et al Toxicology and Applied Pharmacology 1984, 74, 397-410; Willhite et al Journal of National Cancer Institute 1984, 72, 689-695; Willhite et al Toxicology and Applied Pharmacology 1986, 83, 563-575; Howard et al Toxicology and Applied Pharmacology 1988, 95, 122-138).
There exists therefore a need to improve upon the prior art in order to enhance the clinical profile of such therapeutics. Such improvements may be carried out by introducing specially designed functional groups at specific positions on the molecular backbone of the modulator. The novel compounds of this invention address this issue and display enhanced in vitro profiles when compared to compounds of the prior art.